It has been known for some time that for medicinals having at least one chiral center the pharmacological effectiveness of the enantiomers of the racemic mixture may differ substantially. Thus, although the recognition of the desirability of using the pharmacologically and pharmaceutically more acceptable enantiomer is old, nonetheless the use of optically pure medicinals generally is relatively new, simply because of the difficulty and cost of resolution of the racemic mixture and/or the difficulty and cost of asymmetric synthesis of the desired enantiomer. The importance of stereochemical purity may be exemplified by L-propranolol, which is known to be 100 times more potent than its D-enantiomer. Furthermore, optical purity is important since certain isomers actually may be deleterious rather than simply inert. For example, the D-enantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy. However, L-thalidomide was discovered to be a potent teratogen leaving in its wake a multitude of infants deformed at birth.
With recent chemical advances, especially in asymmetric synthesis, has come both an increase in the feasibility of selectively preparing the more acceptable enantiomer of a given chiral medicinal, as well as increasing pressure on the pharmaceutical industry to make available only that enantiomer. An instructive example, pertinent to the subject matter of this invention, is the class of serotonin-uptake inhibitors exemplified by fluoxetine (whose racemate is available as Prozac.TM.), tomoxetine, and nisoxetine, all of which have the structure (as the hydrochloride) ##STR1## where R.sub.3 =4-CF.sub.3, 2-CH.sub.3, and 2-C.sub.2 H.sub.5 O, respectively.
Thus, Skrebnik, Ramachandran & Brown, J. Org. Chem., 53, 2916, 1988, used chirally modified boron compounds in the asymmetric reduction of prochiral ketones. From 3-chloropropiophenone there was prepared S-3-chloro-1-phenyl-1-propanol in 97% enantiomeric purity which then was used as the starting material for the preparation of the corresponding enantiomers of S-tomoxetine and S-fluoxetine. Shortly thereafter, Gao & Sharpless, J. Org. Chem., 53, 4081, 1988, developed an enantioselective synthesis of both enantiomers of tomoxetine and fluoxetine from cinnamyl alcohol via catalytic asymmetric epoxidation and regioselective reduction of the corresponding epooxycinnamyl alcohols. E. J. Corey and G. A. Reichard, Tetrahedron Letters, 30, No. 39, 5207 (1989) outlined a 4-step synthesis of enantiomerically pure fluoxetine from 3-chloropropiophenone in 77-82% overall yield with the key step being the enantioselective catalytic reduction of the ketone to 3-chloro-1-phenyl-1-propanol (CPP) in 99% yield and with 94% enantiomeric selectivity. Recrystallization afforded material of 100% enantiomeric purity with 82% recovery. These authors have recognized that compounds such as CPP are extremely useful in syntheses. The patentees in U.S. Pat. No. 5,104,899 recognized that the S(+)isomer of fluoxetine was the more desirable enantiomer, since it was found not to have certain side effects of the racemate such as nervousness, anxiety, insomnia, and adverse psychological effects. The patentees also recognize that the S-enantiomer had a faster onset of action with a quicker response rate.
The foregoing are examples of enantioselective synthesis. Enantioselective synthesis depends on chiral reagents of high enantiomeric purity which often are quite expensive. Consequently, another general approach is based on the efficient resolution of an early precursor, used as a raw starting material in synthesis, with high enantiomeric purity followed by subsequent conventional synthetic techniques which maintain high enantiomeric purity in intermediates through final product formation. This approach is exemplified by the work of Schneider and Goergens, Tetrahedron: Asymmetry, No. 4, 525, 1992. These authors effected enzymatic resolution of CCP via enzymatic hydrolysis of the racemic acetate in the presence of a lipase from Pseudomonas fluorescens under close pH control with a phosphate buffer. The hydrolysis was halted after about 50% conversion to afford the R-alcohol while leaving unchanged the S-acetate, which subsequently could be hydrolyzed with base to the S-alcohol. From the enantiomerically pure alcohols the enantiomerically pure tomoxetine, fluoxetine, and nisoxetine could be prepared.
The Schneider and Goergens approach highlights a characteristic of methods based on resolution of a racemate which requires our attention. Although in their report the authors used both the R- and S-CPP to prepare, for example, both R- and S-fluoxetine in high optical purity, when one enantiomer is substantially more desirable than the other (see U.S. Pat. No. 5,104,899, supra) in practice only the more desirable enantiomer will be utilized in subsequent synthesis. Unless one is willing to accept the economic burden of discarding the less desirable (or even undesirable) enantiomer--which is half of the starting material! - it is imperative to somehow recycle the undesired enantiomer. Stated concisely, incident to a method of preparing medicinals of high optical purity based on using a raw material of high enantiomeric purity obtained via resolution of its racemate is the requirement of recycling the unwanted enantiomer produced as a byproduct to the resolution stage. This application is directed precisely to this need to afford a cost-effective solution to the preceding problem.